2-benzhydrylidine-delta3-tropene and lower alkyl halide quaternaries



United States Patent 2 BENZHYDRYLlDINE-M-TROPENE AND LOWER ALKYL HALlDEQUATERNARIES Harold E. Zaugg, Lake Forest, and Raymond J. Michaels, Jr.,Mundelein, Ill., assignors to Abbott Laboratories, North Chicago, 111.,a corporation of Illinois No Drawing. Application March 20, 1958 SerialNo. 722,636

4 Claims. (Cl. 260-292) This invention relates to an ester alkaloidderivative, particularly a derivative of tropene and its non-toxicsalts.

The tropene derivative of this invention contains a double bond betweenthe 3 and 4-carbon positions in the ring, and a benzhydrylidine group atthe 4-position as represented by the following structure The nameassigned to the foregoing structure is 2-benzhydrylidine-A -tropene. Thecompound of this invention is prepared by initially reacting cocainewith a phenyl Grignard reagent to prepare the tropane derivative EXAMPLEI Diphenyl- (3-hydroxy-2-tropyl) -carbinol To a stirred solution of 0.7mole of phenylmagnesium bromide in 600 ml. of ether is added a solutionof 0.088 mole of cocaine base in 500 ml. of dry ether. The mixture isstirred and refluxed for 18 hours. After cooling, a solution of 50 gramsof ammonium chloride in 200 ml. of water is added dropwise to thestirred reaction mixture and the product is isolated to give 15.4 grams(51%) of diphenyl-(3-hydroxy-2-tropy1)-carbino1, M.P.

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2 185-l86 C., 23.5, pKa 7.49 (by titration in aqueous methanol).

Anal. calcd. for C H NO .-Calculated: C, 78.05%; H, 7.79%; N, 4.33%.Found: C, 77.98%; H, 7.72%; N, 4.31%.

EXAMPLE II 2-benzhydrylidine-M-tropene A mixture of 8.4 grams (0.026mole) of diphenyl- (3-hydroxy-2-tropy1)-carbinol, 18 ml. of concentratedhydrochloric acid and ml. of glacial acetic acid is refluxed for twohours and then concentrated to dryness under reduced pressure. Theresidue is dissolved in water and made strongly alkaline with 40%aqueous sodium hydroxide. The precipitated oil is taken up in ether anddried over anhydrous sodium sulfate. The mixture is filtered and theether is removed by distillation followed by two distillations of theresidue under reduced pressure to give 4.5 grams of 2-benzhydrylidine-A-tropene, B.P. 201-203" (2.5 mm.), N 1.6338, [a] +548.

Anal. calcd. for C H N.-Calculated: C, 87.76%; H, 7.37%; N, 4.87%.Found: C, 87.94%; H, 7.59%; N, 4.91%.

EXAMPLE III Z-benzhydrylidine-M-tropene methiodide The base of ExampleII (1 gram) is dissolved in 50 ml. of methyl ethyl ketone and refluxedfor two minutes with 2 grams of methyl iodide. The mixture is allowed tostand for two days, after which recrystallization from ethanol yields0.7 gram of 2-benzhydrylidine-A -tropene methiodide, M.P. 281-282 C.,dec. [M +450. v

Anal. calcd. for C H lN.--Calculated: C, 61.54%; H, 5.63%; N, 3.26%.Found: C, 61.57%; H, 5.86%; N, 2.97%.

Others may practice the invention in any of the numerous ways which willbe suggested by this disclosure to one skilled in the art. All suchpractice of the invention is considered to be a part hereof provided itfalls within the scope of the appended claims.

We claim:

1. 2-benzhydrylidine-A -tropene.

2. 2-benzhydrylidine-A- -tropene methiodide.

3. A method for preparing 2-benzhydrylidine-A -tropene comprising theaddition of about 2 moles of a phenyl Grignard reagent to about 1 moleof cocaine base, refluxing said mixture for about 12 hours, isolatingthe base, diphenyl-(3-hydroxy-2-tropyl)-carbinol, dehydrating said basewith a mixture of concentrated hydrochloric acid and glacial acetic acidand isolating the base, 2-benzhydrylidine-A -tropene.

4. A compound selected from the class consisting of 2-benzhydrylidine-A-tropene and the non-toxic lower alkyl halide quaternary ammonium saltsthereof.

Grundmann et al. Feb. 26, 1957 Zrikle July 23, 1957

4. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF2-BENZHYDRYLIDINE-$3-TROPENE AND THE NON-TOXIC LOWER ALKYL HALIDEQUATERNARY AMMONIUM SALTS THEREOF.